Eight inherited neurological disorders have been found to associate with an expansion of a glutamine repeat in the protein products of the disease genes. Increasing evidence has shown that the expanded glutamine repeat causes the disease proteins to aggregate in the nucleus and to abnormally interact with other proteins, Studies of brains from patients with Huntington's disease (HD) and HD animal models have indicated that N- terminal fragments of huntingtin with expanded polyglutamine accumulate in the nucleus and are toxic to neurons. However, the mechanisms of these pathological events remain unknown. The aim of this proposal is to investigate the mechanisms of cellular pathology caused by intranuclear huntingtin with expanded polyglutamine. We will use cellular and animal models to address two important questions: (1) how N-terminal fragments of huntingtin with expanded polyglutamine are accumulated in the nucleus, and (2) how intranuclear mutant huntingtin induces cellular dysfunction. Accordingly, two specific aims will be pursued. Aim 1 is to study how N- terminal huntingtin with expanded polyglutamine is generated and accumulates in the neuronal nucleus and to identify proteins or cellular factors that keep mutant huntingtin in the nucleus. Aim 2 is to investigate how mutant huntingtin may interact with transcription factors and affects gene transcription. These studies will advance our knowledge about the pathogenesis of HD and provide vital information to help develop therapeutic strategies.